Alzheimer's disease (AD) is a devastating illness that will affect an increasing number of older adults in the coming decades unless effective preventive strategies are developed. Therapies that delay the onset of AD by just five years may reduce the prevalence of AD significantly. High blood cholesterol levels in midlife increase the risk of developing AD decades later, possibly via their negative effects on 2-amyloid (A2) metabolism and cerebrovascular dysfunction. Both A2 deposition in the brain and cerebrovascular dysregulation are two early findings in preclinical AD pathology and work synergistically to accelerate neuronal degeneration. Thus, therapies that both reduce A2 levels and improve cerebral blood flow (CBF) may interrupt this cascade effect to delay the development of AD. Use of cholesterol-lowering medications called statins has been associated with a significant reduction in the prevalence of AD in observational studies, suggesting a potentially promising role for statins in AD prevention. Statins lower A2 levels in the cerebrospinal fluid (CSF) and brains of animals and improve CBF in animals, but clinical trials to date have not shown conclusively that statins beneficially modify A2 metabolism or CBF in asymptomatic adults at increased risk for AD. Building upon previous investigations, we propose an 18-month randomized, controlled, double-blind pilot clinical trial evaluating the effects of simvastatin 40 mg daily on CSF A2 levels and cerebral perfusion in asymptomatic adults at high risk for AD due to their parental history of AD and high prevalence of apolipoprotein E 54 (APOE4) allele. For this study, CSF A242 levels will be the primary outcome, but CSF A240, total tau and phosphorylated tau, and other novel CSF biomarkers will also be measured to increase the ability of A242 to predict underlying disease. Quantitative cerebral perfusion will be assessed using arterial spin-labeling magnetic resonance imaging (ASL-MRI). Interim assessments of CSF and MRI biomarkers will be collected to clarify whether longer term statin therapy has a cumulative effect in modifying these markers of AD progression. In addition, this pilot clinical trial will evaluate the impact of changes in CSF A2 metabolism and CBF on cognitive measures. The findings from this pilot clinical trial will help guide the development of pivotal trials ultimately needed to demonstrate clinical efficacy. PUBLIC HEALTH RELEVANCE: If simvastatin improves some of the changes that occur in the brain decades before the onset of AD, these findings would strengthen the evidence that there may be a role for statins in Alzheimer's prevention. If statins prevent or delay the onset of AD, they could have a profound impact not only on the physical and emotional health of millions of individual patients at risk for the disease, but also on their families and caregivers.